The outcome for patients with primary malignant brain tumors remains dismal. Most progression occurs at the primary site despite conventional surgery and radiation therapy +/- chemotherapy. Therefore local control is the critical first step to improve outcome. In addition to the infiltrating destruction caused by these tumors, the non-specific nature of current therapies inevitably contributes to normal brain injury, further clinical decline and compromised quality of life. In response to the dire need for effective, innovative therapies for patients for malignant brain tumors, our center has developed novel therapeutics aimed at tumor-associated molecular targets, including unarmed, radiolabeled and toxin-conjugated monoclonal antibodies (MAbs), MAb fragments and growth factor ligand-toxin conjugates. During the prior SRC grant period, our Phase I and II clinical trials with radiolabeled MAbs, MAb fragments, and toxin conjugates confirmed that such therapeutics are effective and were associated with limited toxicity for both malignant glioma and neoplastic meningitis. Coupled with our goal of achieving local control, we have also completed extensive preclinical and clinical studies to improve systemic therapies, such as overcoming alkylguanine transferase (AGT)-mediated chemoresistance, to ultimately reach all tumor cells throughout the neuraxis. Our HYPOTHESIS is that novel therapeutics aimed at molecular targets will improve local tumor control and when coupled with more effective systemic therapies, ultimately contribute to overall tumor cell eradication while preserving quality of life for patients with malignant brain tumors. The SPECIFIC AIMS of this proposal are: Specific Aim 1. To conduct Phase I and II clinical trials to assess anti-tumor activity and toxicity of: 1) newly developed, tumor-targeted therapeutics against EGFRvIII, GPNMB, MRP3, and the glioma-associated gangliosides 3'-isoLM1 and 3',6'-isoLD1; 2) radioimmunotherapy with lutetium-177; 3) an oncolytic polio/rhinovirus recombinant; and 4) inhibitors of BCNU-induced DNA interstrand crosslink repair. Specific Aim 2. To determine the impact on quality of life of therapeutics evaluated in clinical trials of this project.